Development Of A Theragnostic Compound For The Therapy And Diagnosis Of Glioblastoma
“Theranostic4GLIO”

Introduction

The object and aim of the THERANOSTIC4GLIO research project is the design, synthesis and characterization of a therapeutical molecule for the simultaneous diagnosis and treatment of glioblastoma.Cancer is the leading cause of death worldwide as more than 12 million patients and 7 million deaths worldwide were recorded in 2008, and these numbers increased dramatically to 15 million cases and 8.8 million deaths in 2015.

Glioblastoma is the most common and a more aggressive type of primary brain tumor in adults, involving glial cells and accounting for 52% of all cases of intraxial tumors and 20% of all intracranial tumors. The mean survival is only 12-15 months. Typically, treatment involves surgery, followed by chemotherapy and radiotherapy. The inability to treat glioblastoma is due to the heterogeneity of the tumor, particular characteristics of the interaction of cancer cells with the brain microenvironment and the presence of the blood-brain barrier. The development of a sensitive diagnostic tool for early imaging of cancer cells, even at very early stages, is very important. Cancer imaging technologies include non-invasive imaging techniques such as Magnetic Resonance Imaging (MRL), Computed Tomography (CT), Positron Emission Tomography (PET), Single Photon Emission CT (SPECT), and visual imaging for microscopic tumor detection . In recent years, glioblastoma imaging has been investigated using 99mTc-Tetrofosmin (99mTc-TF), a SPECT tracers, with very good results. Malignant tumors are associated with increased mitochondrial function, thus exhibiting a higher uptake of 99mTc-TF, and this has been demonstrated in patients with gliomas in which higher uptake was found to high-grade tumors contrary to low-grade tumors.

In addition, 99mTc-TF appears to be less affected by the existence of the mechanism of elimination and uptake of chemotherapeutic substances possessing certain cancer cells through p-glycoprotein. In addition, in order to develop a sensitive diagnostic agent for the early imaging of cancer cells even at very early stages, it is also very important to monitor the transfer of cytotoxic agents to cancer cells. Theranostic due to their dual nature (therapeutic + diagnostics) are an innovative and attractive approach and offer a wide variety of applications since they can be developed to provide in the same time diagnosis and treatment. In this way, it is also possible to deliver the desired chemotherapeutic agent to the malignant tumor, but also to simultaneously reveal the mechanism of action. The overall objective of this proposal is to develop an innovative theranostic for the simultaneous diagnosis, based on 99mTc-Tetrofosmin, and treatment of glioblastoma. This proposal will help optimize personalized diagnosis and treatment of cancer by synthesizing several theranostics. Thus, a synthesis of a theranostic consisting of three structural segments, the targeting molecule, the labeling group and the cytotoxic agent will be made. This will be followed by the study of the pharmacokinetic properties of the final theranostic in human plasma and the evaluation of the final theranostic in glioblastoma cell lines and Zebrafish for toxicity studies. Finally, an in vivo imaging study of the theranostic in rats will be performed.

Partners

SYN INNOVATION Laboratories SA (Coordinator)

Department of Chemistry University of Ioannina

Neurosurgical Institute University of Ioannina

National Centre For Scientific Research “Demokritos”

Current Publications

1. Vrachliotis, A., Gaitanis, A., Protonotarios, N. E., Kastis, G. A., & Costaridou, L. (2024). Noninvasive Quantification of Glucose Metabolism in Mice Myocardium Using the Spline Reconstruction Technique. In Journal of Imaging (Vol. 10, Issue 7, p. 170). MDPI AG. https://doi.org/10.3390/jimaging10070170
2. Jonić, N., Koprivica, I., Chatzigiannis, C. M., Tsiailanis, A. D., Kyrkou, S. G., Tzakos, E. P., Pavić, A., Dimitrijević, M., Jovanović, A., Jovanović, M. B., Marinho, S., Castro-Almeida, I., Otašević, V., Moura-Alves, P., Tzakos, A. G., & Stojanović, I. (2024). Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. Molecules (Vol. 29, Issue 13, p. 2988). MDPI AG. https://doi.org/10.3390/molecules29132988
3. Vrettos, E., Kyrkou, S., Zoi, V., Giannakopoulou, M., Chatziathanasiadou, M., Kanaki, Z., Agalou, A., Bistas, V.-P., Kougioumtzi, A., Karampelas, T., Diamantis, D., Murphy, C., Beis, D., Klinakis, A., Tamvakopoulos, C., Kyristis, A., Alexiou, G., & Tzakos, A. (2024). A fluorescent gemcitabine prodrug that follows a nucleoside transporter‐independent internalization and bears enhanced therapeutic efficacy with respect to gemcitabine. Chemistry – A European Journal. Wiley. https://doi.org/10.1002/chem.202401327
4. Zoi, V., Giannakopoulou, M., Alexiou, G. A., Bouziotis, P., Thalasselis, S., Tzakos, A. G., Fotopoulos, A., Papadopoulos, A. N., Kyritsis, A. P., & Sioka, C. (2023). Nuclear Medicine and Cancer Theragnostics: Basic Concepts. Diagnostics (Vol. 13, Issue 19, p. 3064). MDPI AG. https://doi.org/10.3390/diagnostics13193064
5. Marinakis, V., Fokas, A. S., Kastis, G. A., & Protonotarios, N. E. (2023). Chebyshev Interpolation Using Almost Equally Spaced Points and Applications in Emission Tomography. Mathematics (Vol. 11, Issue 23, p. 4757). MDPI AG. https://doi.org/10.3390/math11234757
6. Protonotarios, N. E., Kastis, G. A., Fotopoulos, A. D., Tzakos, A. G., Vlachos, D., & Dikaios, N. (2022). Motion-Compensated PET Image Reconstruction via Separable Parabolic Surrogates. Mathematics (Vol. 11, Issue 1, p. 55). MDPI AG. https://doi.org/10.3390/math11010055

Conferences

Proceedings

1. Protonotarios, N. E., Kalimeris, K., & Kastis, G. A. (2023). Fokas on Medical Imaging: Analytic Reconstructions for Emission Tomography. Chaos, Fractals and Complexity (pp. 169–187). Springer International Publishing. https://doi.org/10.1007/978-3-031-37404-3_11

Presentations

1. Evangelia-Alexandra Salvanou, Stavroula G. Kyrkou, Vasileios-Panagiotis Bistas, Vasiliki Zoi, Maria Giannakopoulou, George A. Alexiou, Athanasios P. Kyritsis, Savvas Thalasselis, Andreas G. Tzakos and Penelope Bouziotis, “Preliminary evaluation of a novel Temozolomide-based molecule radiolabeled with 99mTc as a theranostic agent against glioblastoma”, Oral Presentation: 21st European Symposium on Radiopharmacy & Radiopharmaceuticals Coimbra. Portugal, 18-21 April 2024.
2. Eirinaios Ι. Vrettos, Stavroula G. Kyrkou, Vasiliki Zoi, Maria Giannakopoulou, Maria V. Chatziathanasiadou, Zoi Kanaki,   Adamantia Agalou, Anastasia Kougioumtzi ,  Theodoros Karampelas, Christos M. Chatzigiannis, Dimitris Diamantis, Carol Murphy ,  Dimitris Beis, Apostolos, Klinakis, Constantin Tamvakopoulos, Athanasios P. Kyritsis, George A. Alexiou, Andreas G. Tzakos , “A novel fluorescent Gemcitabine prodrug that localized in lysosomes and bears enhanced therapeutic efficacy with respect to Gemcitabine”, Oral Presentation: The 4th International Electronic Conference on Cancers, 06-08/03/2024, Online
3. N. E. Protonotarios, S. Thalasselis, G. A. Kastis, “SPECT Imaging via Spline-based Inversion of the Attenuated Radon Transform”, Poster Presentation: Chemical Biology Workshop on Drug & Biomarker Discovery, 23-25 November, 2023.
4. E.-A. Salvanou, S. G. Kyrkou, G. A. Alexiou, A. P. Kyritsis, S. Thalasselis, A. G. Tzakos and P. Bouziotis, “99mTc labeling of a novel Temozolomide-based molecule as a theranostic agent against glioblastoma”. Poster Presentation: Chemical Biology Workshop: Drug and Biomarker Discovery, National Hellenic Research Foundation, 23-25 November 2023.
5. Apostolopoulou, L. Gautier, S. G. Kyrkou G. Alexiou, A. P. Kyritsis, S. Thalasselis, A. G. Tzakos, Stephane Roux and P. Bouziotis, “Actinium-225 radiolabeling of gold nanoparticles for therapy of glioblastoma”. Poster Presentation: Chemical Biology Workshop: Drug and Biomarker Discovery, National Hellenic Research Foundation, 23-25 November 2023.
6. Vrettos E.I., Kougioumtzi A., Karampelas T., Kanaki Z., Agalou A., Chatziathanasiadou M.V., Chatzigiannis C.M., Diamantis D., Beis D., Klinakis A., Tamvakopoulos K., Zoi V., Giannakopoulou M., Voulgaris S., Bouziotis P., Thalasselis S., Fotopoulos A., Alexiou G.A., Tzakos A.G., “A Novel Agent based on Gemcitabine that displays antiglioma effect”, Poster Presentation: International Conference – Neurosurgery Novel Advancements, September 01-03, 2023, Ioannina, Greece.
7. Zoi V., Giannakopoulou M., Alexiou G.A., Bouziotis P., Thalasselis S., Tzakos A.G., Fotopoulos A., Papadopoulos A.N., Kyritsis A.P., Sioka C., “The role of theragnostic in PET and SPECT”, Poster Presentation: International Conference – Neurosurgery Novel Advancements, September 01-03, 2023, Ioannina, Greece
8. Vrettos E.I., Kougioumtzi A., Karampelas T., Kanaki Z., Agalou A., Chatziathanasiadou M.V., Chatzigiannis C.M., Diamantis D., Beis D., Klinakis A., Tamvakopoulos K., Zoi V., Giannakopoulou M., Voulgaris S., Bouziotis P., Thalasselis S., Fotopoulos A., Alexiou G.A., Tzakos A.G., “Novel Antiglioma theragnostic agent based on Gemcitabine”, Oral Presentation: 36th Annual Congress of the Hellenic Neurosurgical Society & Joint Meeting with the Italian Society of Neurosurgery (SINch), German Society of Neurosurgery (DGNC), Cyprus Neurosurgical Society, 29/6-02/07/2023, Athens, Greece.
9. M. V. Chatziathanasiadou, A. D. Kostagianni, A. D. Tsiailanis, S. Thalasselis, V. Cherezov, G. Alexiou, G. B. Sivolapenko, M. A. El Mubarak, P. Bouziotis, G. A. Kastis, A. Klinakis, T. Crook, N. Syed, A. G. Tzakos, “Targeting the Tumor Microenviroment in Gliomas”, Poster Presentation: 19th Hellenic Symposium on Medicinal Chemistry (HSMC-19), Patra, Greece, 9-12 March, 2023.